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The Journal of Neuroscience, March 12, 2008, 28(11):2892-2902; doi:10.1523/JNEUROSCI.5589-07.2008

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Cellular/Molecular
P2Y₁₂ Receptor Upregulation in Activated Microglia Is a Gateway of p38 Signaling and Neuropathic Pain

Kimiko Kobayashi, Hiroki Yamanaka, Tetsuo Fukuoka, Yi Dai, Koichi Obata, and Koichi Noguchi

Department of Anatomy and Neuroscience, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan

All correspondence should be addressed to Dr. Koichi Noguchi, Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan. Email: noguchi{at}hyo-med.ac.jp

Microglia in the spinal cord may play an important role in the development and maintenance of neuropathic pain. A metabotropic ATP receptor, P2Y₁₂, has been shown to be expressed in spinal microglia constitutively and be involved in chemotaxis. Activation of p38 mitogen-activated protein kinase (MAPK) occurs in spinal microglia after nerve injury and may be related to the production of cytokines and other mediators, resulting in neuropathic pain. However, it remains unknown whether any type of P2Y receptor in microglia is involved in the activation of p38 MAPK and the pain behaviors after nerve injury.

Using the partial sciatic nerve ligation (PSNL) model in the rat, we found that P2Y₁₂ mRNA and protein increased in the spinal cord and peaked at 3 d after PSNL. Double labeling studies revealed that cells expressing increased P2Y₁₂ mRNA and protein after nerve injury were exclusively microglia. Both pharmacological blockades by intrathecal administration of P2Y₁₂ antagonist and antisense knockdown of P2Y₁₂ expression suppressed the development of pain behaviors and the phosphorylation of p38 MAPK in spinal microglia after PSNL. The intrathecal infusion of the P2Y₁₂ agonist 2-(methythio) adenosine 5'-diphosphate trisodium salt into naive rats mimicked the nerve injury-induced activation of p38 in microglia and elevated pain behaviors.

These data suggest a new mechanism of neuropathic pain, in which the increased P2Y₁₂ works as a gateway of the following events in microglia after nerve injury. Activation of this receptor by released ATP or the hydrolyzed products activate p38 MAPK pathway and may play a crucial role in the generation of neuropathic pain.

Key words: P2Y₁₂; ATP; ADP; microglia; p38 MAPK; neuropathic pain; spinal cord

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Received Sept. 4, 2007; revised Jan. 29, 2008; accepted Jan. 30, 2008.

All correspondence should be addressed to Dr. Koichi Noguchi, Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan. Email: noguchi{at}hyo-med.ac.jp

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